The organization of MHC genes from a collection of wild mice has been examined. These mice, collected from all over the world, have been separated in evolution for periods of up to 15 million years, and represent 4 sub-genera, 3 species, and 2 sub-species. It has been demonstrated that changes in the number of class I MHC genes can be observed to occur over short periods of evolutionary time, namely between closely related species. Further, these changes do not occur uniformly throughout the class I gene family, but can be restricted to sub-sets of these genes. In contrast, the class II genes (A Alpha, E Alpha, A Beta and E Beta) have been conserved with respect to number and also relatively well conserved with respect to restriction fragment length polymorphisms. Of particular interest was the finding that the genomic fragment corresponding to the EBeta2 gene was highly conserved in all of the animals tested. This fragment could also be identified by a human SBBeta probe. Based on these observations we predict that the EBeta2 gene is a genetically functional gene.